Cisplatin: From Platinum to Precision – A Comprehensive Pharmacology Review

Cisplatin remains the cornerstone of platinum‑based chemotherapy, yet its clinical impact extends far beyond a single drug class. In 2023, oncology services in the United States administered over 80,000 cisplatin cycles, a figure that underscores its continued relevance for testicular, ovarian, bladder, and lung cancers. Despite its efficacy, the drug’s narrow therapeutic index demands meticulous dosing, hydration, and monitoring. This article dissects cisplatin’s pharmacology, from its molecular genesis to bedside practice, to equip pharmacy and medical students with a robust, practice‑ready knowledge base.

Introduction and Background

First synthesized in 1965 by Barnstead and colleagues, cisplatin (C12H24Cl2N2O4) entered clinical trials in the early 1970s and received FDA approval in 1978 for metastatic testicular cancer. Its discovery was a landmark moment, transforming platinum from a toxic metal into a therapeutic agent. Since then, cisplatin has been incorporated into multimodal regimens for a spectrum of solid tumors, achieving cure rates of 70–80% in early‑stage germ cell tumors and improving survival in advanced malignancies.

Globally, cisplatin accounts for an estimated 5–10% of all chemotherapy prescriptions. In the United States, it is the most frequently prescribed platinum agent, with a cumulative patient exposure exceeding 1.2 million courses annually. The drug’s utility is tempered by cumulative toxicity, which limits the total lifetime dose to 4,000–5,000 mg/m2 in many protocols. Consequently, clinicians often switch to carboplatin or oxaliplatin when renal or auditory function deteriorates.

Cisplatin belongs to the class of alkylating agents, specifically a platinum‑based chemotherapeutic. Unlike nitrogen mustard or nitrogenous base analogs, cisplatin exerts its cytotoxicity through covalent binding to DNA, forming intra‑ and inter‑strand crosslinks that impede replication and transcription. The drug’s mechanism is unique in that it does not target a single receptor but rather exploits the cell’s inherent DNA repair pathways, rendering it effective against rapidly dividing tumor cells while sparing quiescent tissues to a degree.

Mechanism of Action

DNA Cross‑Linking

Upon entering the cell, cisplatin undergoes aquation, replacing chloride ligands with water molecules. The resulting highly reactive aqua species forms covalent bonds with the N7 position of guanine residues, generating 1,2‑intrastrand crosslinks that distort the helical structure by 30 degrees. These lesions block the progression of DNA polymerases and RNA polymerases, triggering replication fork stalling and transcriptional arrest. The crosslink density correlates with cytotoxic potency, explaining the drug’s effectiveness against highly proliferative tumors.

Activation and Cellular Uptake

Cisplatin’s uptake is mediated by both passive diffusion and active transporters such as copper transporter 1 (CTR1) and organic cation transporter 2 (OCT2). Once inside, the drug is activated by hydrolysis in the lower chloride environment of the cytosol, forming the reactive species that targets DNA. The presence of high intracellular glutathione can conjugate cisplatin, forming inactive complexes that contribute to resistance. Thus, variations in transporter expression and glutathione levels influence therapeutic response.

Inhibition of DNA Repair and Cell Cycle Arrest

Cells initiate nucleotide excision repair (NER) to remove cisplatin adducts, but the repair machinery often fails to fully excise the lesions before replication. Persistent damage activates p53 and ATM/ATR kinases, leading to cell cycle arrest at G1/S or G2/M checkpoints. If the damage is irreparable, apoptosis ensues via the intrinsic mitochondrial pathway, mediated by BAX activation and cytochrome c release. The net result is selective tumor cell death, though normal cells with high turnover (e.g., renal proximal tubules, cochlear hair cells) also succumb, giving rise to nephrotoxicity and ototoxicity.

Clinical Pharmacology

Pharmacokinetics of cisplatin are characterized by rapid distribution into tissues, a large volume of distribution (0.3 L/kg), and a biphasic elimination pattern. The initial distribution half‑life is 30–40 minutes, followed by a terminal half‑life of 30–100 hours, reflecting slow clearance from deep compartments. Renal excretion accounts for approximately 80% of the dose, with a glomerular filtration rate of 30–40 mL/min in healthy adults. Non‑renal elimination via hepatic metabolism is minimal, but the drug undergoes conjugation with glutathione and cysteine, forming inactive mercapturic acid derivatives.

Pharmacodynamics reveal a dose‑dependent relationship between plasma concentration and cytotoxic effect. The therapeutic window is narrow; a 2–3 mg/m2 incremental increase can double the risk of nephrotoxicity without proportionally enhancing tumor kill. Cisplatin’s cytotoxicity is measured by the area under the concentration–time curve (AUC), with an AUC of 5–10 mg·h/L correlating with optimal response in testicular cancer. Clinicians often target an AUC of 6 mg·h/L using a 3–5 day infusion schedule to balance efficacy and safety.

Therapeutic Applications

FDA‑approved indications for cisplatin include: testicular germ cell tumors, ovarian carcinoma, non‑small cell lung cancer, squamous cell carcinoma of the head and neck, metastatic bladder cancer, and certain sarcomas. The drug is commonly combined with etoposide, bleomycin, or gemcitabine, depending on tumor type. Typical dosing ranges from 20–100 mg/m2 per cycle, administered intravenously over 1–2 hours with pre‑infusion hydration of 3–4 L of isotonic saline to mitigate nephrotoxicity.

Off‑label evidence supports cisplatin in metastatic colorectal cancer (as part of FOLFOX regimens), cervical cancer, and refractory metastatic melanoma. In radiation oncology, cisplatin serves as a radiosensitizer in nasopharyngeal carcinoma and anal cancer, enhancing DNA damage induced by ionizing radiation. Emerging data suggest a role in immunotherapy combinations, where cisplatin may modulate the tumor microenvironment to improve checkpoint inhibitor efficacy.

In pediatrics, dosing is calculated using body surface area with a maximum cumulative dose of 4,000 mg/m2 to prevent long‑term auditory and renal sequelae. Geriatric patients exhibit higher susceptibility to nephrotoxicity; dose adjustments and extended hydration protocols are mandatory. Renal impairment necessitates dose reduction proportional to creatinine clearance, with a threshold of <30 mL/min prompting discontinuation. Hepatic impairment has minimal impact, but caution is advised in cirrhotic patients due to altered protein binding. Pregnancy category D mandates strict avoidance unless benefits outweigh risks, and fetal monitoring is essential if exposure occurs.

Adverse Effects and Safety

Nephrotoxicity occurs in 30–50% of patients, presenting as acute tubular necrosis with rising serum creatinine and oliguria. Ototoxicity affects 10–20% of patients, manifesting as high‑frequency sensorineural hearing loss that can be irreversible. Neurotoxicity, though less frequent (5–10%), presents as peripheral neuropathy with paresthesias and gait instability. Myelosuppression is dose‑dependent, with neutropenia in 20–30% of patients, necessitating growth factor support. Non‑specific side effects include nausea, vomiting, and alopecia.

Black‑box warnings include nephrotoxicity, ototoxicity, and hypersensitivity reactions. Hypersensitivity can progress to anaphylaxis, especially on repeat cycles, necessitating premedication with antihistamines and steroids. The drug’s cumulative dose limits are strictly enforced to prevent irreversible organ damage. Additionally, cisplatin is teratogenic; strict contraception is required for both male and female patients during therapy and for 6 months thereafter.

Baseline labs include serum creatinine, electrolytes, complete blood count, liver function tests, and audiometry. During therapy, serum creatinine and electrolytes are checked daily for the first 48–72 hours, then twice weekly. Audiologic monitoring is recommended before each cycle and at 3 and 6 months post‑therapy. Blood counts are obtained prior to each cycle, with granulocyte colony‑stimulating factor prophylaxis considered for high‑risk patients.

Absolute contraindications include known hypersensitivity to cisplatin, severe renal impairment (creatinine clearance <30 mL/min), uncontrolled hypertension, and pregnancy. Relative contraindications encompass severe hepatic dysfunction, uncontrolled electrolyte disturbances, and concurrent use of high‑dose nephrotoxic agents. In patients with a history of severe hearing loss, the risk–benefit ratio must be carefully weighed.

Clinical Pearls for Practice

• Hydration is the single most effective nephroprotection strategy; aim for 3–4 L of isotonic saline before, during, and after infusion.
• Pre‑infusion alkalinization with sodium bicarbonate (1 mEq/kg) reduces cisplatin‑induced nephrotoxicity by promoting renal excretion.
• Administer antihistamines and steroids 30 minutes before infusion to mitigate hypersensitivity reactions, especially on cycle 2 and beyond.
• Use the “C‑Dose” mnemonic: C for cisplatin, D for dose‑adjusted based on creatinine clearance, and E for electrolyte monitoring.
• Schedule audiometry at baseline, after every third cycle, and at 6 months post‑therapy to detect early ototoxicity.
• Avoid high‑dose vitamin C supplements (>500 mg/day) during cisplatin therapy to preserve chemotherapeutic efficacy.
• Consider carboplatin or oxaliplatin as substitutes when cumulative nephrotoxicity or ototoxicity thresholds are approached.

Comparison Table

Exam‑Focused Review

Students frequently encounter questions that ask to differentiate cisplatin from carboplatin and oxaliplatin based on side‑effect profiles. Key differentiators include: nephrotoxicity (cisplatin > carboplatin), ototoxicity (cisplatin > oxaliplatin), and myelosuppression (carboplatin > cisplatin). Recall the mnemonic “C‑N‑O” (Cisplatin nephrotoxicity; Carboplatin myelosuppression; Oxaliplatin neuropathy). USMLE Step 2 CK often tests the mechanism: cisplatin forms 1,2‑intrastrand crosslinks that block DNA polymerase, whereas carboplatin forms mainly inter‑strand crosslinks. NAPLEX questions may focus on hydration protocols and the importance of sodium bicarbonate administration.

Common exam question stems include: “A 45‑year‑old man with metastatic testicular cancer receives cisplatin. Which of the following is the most appropriate monitoring strategy?” Options include: routine audiometry, daily creatinine, weekly CBC, prophylactic antibiotics. The correct answer is routine audiometry and daily creatinine. Another stem: “Which side effect is most likely to occur with carboplatin?” The answer: myelosuppression.

Must‑know facts: 1. The therapeutic index of cisplatin is narrow; small dosing errors can lead to irreversible nephrotoxicity. 2. Hydration with isotonic saline and bicarbonate is essential for all patients. 3. Hypersensitivity reactions are cumulative; premedication is mandatory after the first cycle. 4. Ototoxicity is irreversible and dose‑dependent; baseline audiometry is mandatory. 5. Cisplatin is teratogenic; contraception is required for both sexes.

Key Takeaways

1. First‑line platinum agent for testicular, ovarian, bladder, and lung cancers.
2. Mechanism: DNA cross‑linking via platinum adducts that impede replication.
3. Pharmacokinetics: large volume of distribution, biphasic elimination, renal excretion dominates.
4. Therapeutic window is narrow; dose adjustments based on creatinine clearance are critical.
5. Nephrotoxicity and ototoxicity are the most common dose‑limiting toxicities.
6. Aggressive hydration and sodium bicarbonate reduce renal injury.
7. Baseline and periodic audiometry are mandatory for early ototoxicity detection.
8. Hypersensitivity reactions necessitate premedication from cycle two onward.
9. Pregnancy category D; strict contraception required.
10. Clinical pearls: use the “C‑Dose” mnemonic to remember hydration, dose adjustment, and electrolyte monitoring.

Remember that cisplatin’s life‑saving potential is matched only by its toxicity; meticulous hydration, monitoring, and patient education are the cornerstones of safe therapy.